Fragile X syndrome (FXS) results from a trinucleotide repeat expansion (full mutation > 200 CGG repeats) in the in the 5' untranslated region of the fragile X mental retardation 1 gene (FMR1) located at Xq27.3. This expansion leads to a reduction or absence of the gene's protein product, the FMR1 protein (FMRP), ultimately causing cognitive and behavioral impairments that are characteristic of the syndrome. The presence of significant problems of hyperarousal, social anxiety and withdrawal, social deficits with peers, abnormalities in communication, and gaze aversion is now very well documented in FXS. There is also an abundance of prior research pointing to the amygdala as a place to look in the brain for dysfunction related to anxiety. We propose to use, structural MRI measurements, probes of the amygdala, including fMRI to fear and anger faces and fear potentiated startle, to investigate amygdala dysfunction in FXS. In addition, we will examine relations between function of the FMR1 gene, amygdala volume and function, and neuropsychological measures of social cognition and reciprocity in children and adolescents with FXS. Establishing the presence of amygdala dysfunction in FXS will help us lay the stepping stones for future treatment studies which target the mGluR pathway, and animal research that is ongoing in this area give us abundant hope that pharmacological interventions targeting this pathway can lead to improved function in these individuals. Our proposal involves seeking this information in children and adolescents with FXS, in an effort to target the segment of the population that is perhaps most in need of intervention. The uniqueness and strengths of this proposal lie first in its use of multi- method levels of analysis. The combination of fMRI, physiological, and molecular data will provide us with a very rich picture of amygdala function in young individuals with FXS. We also have excellent access to the FXS population thanks to the extremely well-established fragile X Clinic at the U.C. Davis M.I.N.D. Institute headed by Randi Hagerman, a co-investigator on this grant. Lastly, we are following solid "leads" in the literature that move the field toward real-life treatment consequences for anxiety in FXS. The presence of severe anxiety is a significant problem in FXS, and an abundance of prior research points to the amygdala as a place to look in the brain for dysfunction related to this anxiety. We will use volumetric measurement as well as functional probes of the amygdala (fMRI and fear potentiated startle) to help determine whether amygdala dysfunction, which could be related to the severe anxiety symptoms suffered by so many of these patients, is present in FXS. Establishing this dysfunction will help us lay the stepping stones for future treatment studies, and animal research that is ongoing in this area give us abundant hope that pharmacological interventions targeting this pathway can lead to improved function in these individuals. Our proposal involves seeking this information in children and adolescents with FXS, in an effort to target the segment of the population that is perhaps most in need of intervention. [unreadable] [unreadable] [unreadable]